The proposed studies are of initiation, progression and regression of atherosclerotic lesions in three swine models. The objectives are (1) to determine some of the relationships among arterial smooth muscle cell (SMC) deaths, SMC births, endothelial integrity, hyperlipidemia (HL) size of lesions, extent of foci of lipid-rich necrotic debris and arterial tissue cholesterol concentration; (2) to extend studies of division patterns in progressing lesions from the initial 60 days already studied to longer periods in order to determine whether the heterogeneity of cell division potential observed in the earliest period persists during further growth of the lesions to such an extent that foci of monoclonal origin might eventually develop; (3) to begin to investigate the role of platelet phenomena in the initiation and progression of lesions. The lesions in the 3 swine models are produced respectively by (1) HL diets alone, (2) HL diets plus initial endothelial cell (EC) denudation, (3) normo-lipidemic (NL) diets plus EC-denudation. The 3 models permit us to investigate many parameters in contrasting situations. Methods of study include tritiated thymidine (3HTdR) autoradiography with labelling indices and mathematical analyses of grain count data at successive time intervals for cell death rates and division patterns; quantitative light and electron microscopy with measurements of lesion size and extent of necrosis and evaluation of status of SMC and EC; chemical analyses of cholesterol concentration; and production and use of anti-swine-platelet antibodies. A hypothetical scheme for initiation, progression and regression of atherosclerotic lesions is presented in the application in some detail. The experiments are designed to permit us to test a number of the hypotheses and assumptions that are a part of the suggested evolutionary scheme. Results should either provide support for the hypotheses or point the direction for specific changes in the scheme.